1. Field of the Invention
The present invention relates to mammalian glucagons like peptide-1 (GLP-1) receptor agonists, such as GLP-1 mimetibody constructs, specified portions and variants specific for biologically active proteins, fragment or ligands, GLP-1 receptor agonist encoding and complementary nucleic acids, host cells, and methods of making and using thereof, including improving insulin sensitivity or lipid profiles in obesity related disorders and related therapeutic formulations, administration and devices.
2. Related Art
Recombinant proteins are an emerging class of therapeutic agents. The use of recombinant proteins as potential therapeutics have provided an opportunity for advances in therapeutic protein formulations, also including the use of chemical modifications. Such modifications can potentially enhance the therapeutic utility of therapeutic proteins, potentially such as by increasing serum half lives (e.g., by blocking their exposure to proteolytic enzymes), enhancing biological activity, and/or reducing unwanted side effects. One such modification is the use of immunoglobulin fragments fused to receptor proteins, such as enteracept. Fusion proteins have also been constructed using the antibody Fc domain in an attempt to provide a longer half-life or to incorporate functions such as Fc receptor binding, protein A binding, and complement fixation.
Obesity is a chronic disease manifested by the excess of fat mass in proportion to body size. Approximately one third of Americans are over-weight based on Body Mass Index (BMI>25 kg/m2), and obesity is considered to be reaching epidemic proportions. The importance of obesity's threat to health is emphasized by the fact that obesity is an underlying cause or a risk factor for developing other diseases such as Type 2 Diabetes, cardiovascular disease, osteoartritis, and sleep apnea. Even a modest decrease in body weight (5-10% of initial body weight) may significantly decrease risk factors for developing obesity-associated diseases and improve metabolic syndrome conditions characterized by obesity, atherogenic dyslipidemia, raised blood pressure and insulin resistance.
The need to treat obesity is widely recognized and efforts are being made by all major pharmaceutical companies to develop a successful therapy. Obesity is currently treated by: 1) life style changes, 2) three drugs currently on the market (Phentramine, Orlisata and Sibutramine) that have a modest effect on weight loss and are associated with significant side effects and 3) by surgery.
Glucagon-like peptide-1 (GLP-1) is a 30 amino acid hormone secreted from gut endocrine cells in response to nutrient ingestion. GLP-1 travels through the circulation and binds to the GLP-1 receptor on the pancreas, resulting in an increase in insulin secretion. In addition, it has been shown that GLP-1 reduces gastric emptying which decreases the amount of glucose that is released into the circulation. These actions combine to lower blood glucose levels. Thus, the mechanism of biological activity of GLP-1 suggests that it could be an attractive therapeutic for the treatment of type 2 diabetes. GLP-1 also has the potential to treat obesity. Several studies have shown that GLP-1 administered either peripherally or intracerebroventricularly (ICV) decreases food intake in animal models. A study in humans delivering GLP-1 continuously for five days in obese, diabetic patients resulted in a reduction in food intake and a reduction in body weight. However, GLP-1 is not being developed as a therapeutic because of its exceptionally short half-life (T1/2˜1-2 min). It is rapidly degraded by dipeptidyl protease (DPP-IV), thus reducing the length of the peptide by 2 amino acids at the N-terminus and inactivating it.
There are several GLP-1 analogues that are currently in development or on the market. Byetta™ is a recently marketed GLP-1 analogue developed by Amylin and Eli Lilly. It was first identified in the saliva of the gila monster lizard, and is 53% identical to GLP-1. Byetta™ is resistant to DPP-IV, yet it still requires twice daily pre-prandial dosing partially due to its short in vivo half-life (less than 30 minutes). During clinical trials where Byetta™ was evaluated as a therapy for Type 2 Diabetes, HbAlc levels were lowered approximately 1% following 82 weeks of treatment. Interestingly, patients taking Byetta™ had a sustained decrease in body weight (5-10 pounds) during the course of the study, supporting the theory that GLP-1 analogues have potential for the treatment of obesity. Liraglutide is a lipidated GLP-1 analogue being developed by Novo Nordisk, and it is currently in clinical trials. Based upon the pharmacokinetics of the molecule, it is anticipated that liraglutide will be dosed once daily. A GLP-1 therapy that has an increased half-life such that it could be dosed once weekly or monthly would have a significant advantage over other GLP-1 peptides in development.
Diabetes is a growing epidemic that is estimated will affect over 300 million people by the year 2025 pending an effective pharmaceutical cure. Type 2 diabetes accounts for 90-95% of all cases. Complications resulting from sustained elevated plasma glucose levels include cardiovascular disease, nephropathy, neuropathy, and retinopathy. Current treatments for diabetes are associated with a variety of deleterious side effects including hypoglycemia and weight gain. In addition, current treatments for type 2 diabetes do not cure the disease but simply prolong the time until patients require insulin therapy.
Glucagon like peptide-1 (GLP-1) is a 30-amino acid peptide secreted from the L-cells of the intestine following food digestion. Because of a spectrum of favorable anti-diabetic actions including glucose-dependent insulinotropic action, an effect to slow gastric emptying, and a role in lowering food intake and body weight, GLP-1 has been widely explored as a potential therapy for treating type 2 diabetes. However, native GLP-1 is not a viable therapeutic because it is rapidly inactivated in vivo by the protease DPP-IV with a half life is less than 2 minutes. Exenatide is a DPP-IV resistant GLP-1 analogue currently approved for treatment of Type 2 diabetes. It is a small peptide that requires twice daily preprandial dosing because its in vivo half life is less than 30 minutes.
In addition to the pharmacodynamic effects described above, both GLP-1 and exenatide positively affect the peripheral actions of insulin. Euglycemic hyperinsulinemic clamp studies in diabetic rats showed that chronic, but not acute administration of GLP-1 or exenatide leads to a significant improvement in insulin sensitivity.
Accordingly, there is a need to provide improved and/or modified versions of GLP-1 therapeutic proteins, which overcome one or more of these and other problems known in the art.